Internal medical devices for delivery of therapeutic agents in conjunction with a source of electrical power is the subject of co-pending U.S. patent application Ser. No. 12/077,603 (published as U.S. Patent Application Publication No. 2008/0262412) to Atanasoska et al. (hereinafter “the '603 application”), filed Mar. 20, 2008, which is a continuation of U.S. patent application Ser. No. 11/055,930 (now U.S. Pat. No. 7,850,645). These applications describe processes for delivering a therapeutic agent to a location within a blood vessel. The disclosures of these applications are expressly incorporated herein by reference.
The '603 application describes devices for delivery of therapeutic agents to a diseased location based on electric field effects (i.e., delivery is electrically assisted), such as iontophoresis, electroporation, or both. The '603 application generally relates to internal drug delivery devices which contain a source of therapeutic agents, electrodes and power sources for applying voltages across the first and second electrodes. The power sources may be adapted, for example, to promote electrically assisted therapeutic agent delivery within a subject, including electroporation and/or iontophoresis. The therapeutic agent sources are polymeric regions that contain one or more types of electrically conductive polymers and one or more types of charged therapeutic agents or are polymeric regions that contain one or more types of ion-conductive polymers and one or more types of charged therapeutic agents. By placing the therapeutic agent within a polymer region, movement of the therapeutic agent is restricted and thus more precise local dosing of the therapeutic agent is possible. This design is also advantageous in that it allows one to provide different therapeutic agents or different therapeutic agent dosages for different sections of the device, which can be beneficial in various instances (e.g., where vulnerable plaque is located on one side of a vessel).
Iontophoresis is an electrochemical process by which an electric field is used as a driving force to move a drug into a subject. This technique typically requires two or more electrodes for creating an electric field as well as a drug that carries a net electrical charge at the local physiological pH.
Electroporation methods use short, high-voltage pulses to create transient pores in the cell membranes or in organelles within the cells. This transient, permeabilized state can be used to load cells and organelles with a wide variety of therapeutic agents, for example, genes, proteins, small molecule drugs, dyes, tracers, and so forth.
Voltage may be applied to at least temporarily retain the therapeutic agent within the device (e.g., via iontophoresis of a charged therapeutic agent in the direction of an internal electrode). Voltage may be applied to release the therapeutic agent (e.g., via iontophoresis of a charged therapeutic agent in the direction of an electrode that is external to the therapeutic agent source, or via neutralization of a conductive polymer which leads to expulsion of a charged therapeutic agent from the device). The voltage also may be applied to promote electroporation.
Iontophoretic retention and release can be induced by application of a variety of electrical stimuli including: (a) constant current, (b) constant voltage, (c) current scan/sweep, e.g., via a single sweep or multiple sweeps, (d) voltage scan/sweep, e.g., via a single sweep or multiple sweeps, (e) current square waves or other current pulse wave forms, (f) voltage square waves or other voltage pulse wave forms including exponential voltage output pulses, and (g) a combination of different current and voltage parameters.
For electroporation, high voltage pulses are generally used to create the transient pores within cells exposed to the electric field, allowing the cells to be loaded with therapeutic agent (e.g., due to diffusion, migration or both). The density and size of the transient open pores of the cell membrane depend, for example, on the electric field parameters and polarity. This can be used to tailor the entry of various therapeutic agents of various sizes into the cell membranes or into organelles within the cells.
The '603 application describes electrodes adapted to have tissues of a subject positioned between them upon deployment of the medical device within the subject, such that an electric field may be generated, which has a vector that is directed into the tissue. Furthermore, the therapeutic agent sources are adapted to introduce the one or more therapeutic agents into the as-generated electric field. This may result, for example, in increased electroporation efficiency, increased iontophoresis efficiency (e.g., where one or more charged therapeutic agents are employed), or both.
The '603 application also describes ion-conductive polymeric regions, which are polymeric regions that permit movement of ions and the movement of charged therapeutic agents. Like other ionic species, charged therapeutic agents move in response to concentration gradients and in response to electric fields. In addition to allowing ion movement, ion-conductive polymeric regions are also capable of maintaining therapeutic agents in an ionized form, as opposed to a charge-neutral form. Charge-neutral species are generally not transported in response to an electric field. Polymers suitable for maintaining therapeutic agents in ionized form commonly have cation and/or anion coordinating sites, which are capable of forming complexes with ions, or they are themselves ionized. Polyelectrolytes may be employed as ion conductive polymers. Polyelectrolytes are polymers having multiple (e.g., 5, 10, 25, 50, 100, or more) charged sites (e.g., ionically dissociable groups).
The '603 application also describes conductive polymers, such as polypyrrole. Conductive polymers commonly feature a conjugated backbone (e.g., a backbone containing an alternating series of single and double carbon-carbon bonds). Conductive polymers are typically semi-conductors in their neutral state. However, upon oxidation or reduction of the polymer to a charged state (e.g., polypyrrole is positively charged when oxidized and is neutral when reduced), the electrical conductivity is understood to be changed from a semi-conductive regime to a semi-metallic regime. Oxidation and reduction are believed to lead to charge imbalances that, in turn, can result in a flow of ions into or out of the material. These ions typically enter/exit the material from/into an ionically conductive medium associated with the polymer. For example, it is well known that dimensional changes are effectuated in electroactive polymers, including conductive polymers, by the mass transfer of the ions (which are surrounded by a shell of water molecules) into or out of the polymers. The mass transfer of ions into and out of the material leads to an expansion or contraction of the polymer, delivering significant stresses (e.g., on the order of 1 MPa) and strains (e.g., on the order of 30%).
The fact that oxidation and reduction of conductive polymers is associated with the flow of ions into or out of the material makes these materials useful for retention and/or delivery of charged therapeutic agents. The properties of polypyrroles and other conductive polymers allow them to provide a mechanical component to the therapy, making them particularly desirable for delivery of charged therapeutic agents, for example, in conjunction with electroporation procedures.